This study suggests that smoking cigarettes statistically significantly contributes to MSI in colon tumors. We estimate that approximately 21% of MSI in colon tumors may be attributable to cigarette smoking.

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It has been proposed that dietary factors such as folate, alcohol and methionine may be associated with colon cancer because of their involvement in DNA methylation processes. Data from a large population-based case-control study of incident colon cancer were used to evaluate whether intake of dietary, obesity, physical activity and nonsteroidal antiinflammatory drugs are associated with a CpG island methylator phenotype (CIMP). The BRAF V600E mutation and 5 CpG island markers (MINT1, MINT2, MINT31, p16 and hMLH1) were assessed in 1154 cases of colon cancer. We hypothesized that dietary factors involved in DNA methylation, cruciferous vegetables and use of aspirin/NSAIDs would be associated with CIMP-high tumors. Dietary folate, vitamins B 6 and B 12 , methionine and alcohol were not associated with increased likelihood of colon tumors with the CIMP-high (2 or more markers methylated) phenotype. Dietary fiber, physical activity and aspirin and other nonsteroidal antiinflammatory drugs were inversely associated with both CIMP-low and CIMP-high tumors. Our results also suggested non-CIMP pathways as well. Obese individuals were at 2-fold increased risk of having a CIMPlow tumor. Alcohol was associated with an increased risk of tumors that were MSI1 and CIMP-low. In the presence of smoking 20 or more cigarettes per day, use of NSAIDs did not protect against a BRAF mutation. Our data suggest multiple pathways to colon cancer. They do not support a unique role for dietary folate, alcohol, vitamins B 6 and B 12 and methionine in a CpG island methylator phenotype. ' 2006 Wiley-Liss, Inc.Key words: BRAF CIMP; CpG island; colon cancer; folate; alcohol; methionine; NSAIDs Microsatellite instability is the expansion or contraction of short nucleotide repeats. This phenomenon was originally observed in tumors from individuals with hereditary nonpolyposis colon cancer (HNPCC), where it was found to be the result of inherited germline mutations of mismatch repair genes, mostly hMLH1 and hMSH2. Subsequently, it was found that 15% of sporadic colon tumors exhibit microsatellite instability, and in most of these tumors, the genetic basis for instability was acquired hypermethylation of the hMLH1 promoter with subsequent transcriptional silencing of this gene.1 These observations have led to the definition of a new molecular pathway for colon carcinogenesis.2 In this pathway, hypermethylation of CpG islands near promoter regions of genes and subsequent transcriptional silencing, rather than mutation or deletion of coding regions, is responsible for tumor suppressor gene inactivation. It is now recognized that 30-50% of colon cancers are characterized by a CpG island methylator phenotype (CIMP) in which numerous CpG islands are methylated and tumor suppressor genes such as the cell cycle regulator p16 are inactivated. [3][4][5][6] Methylation is thought to be a relatively early event in colon carcinogenesis, as it has been identified in adenomatous polyps. CIMP-positive tumors that subsequently inactivate the hMLH1 gene, probably...

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10−14), 18q21.33 (BCL2, P = 7.76 × 10−11), 11p15.5 (C11orf21, P = 2.15 × 10−10), 4q25 (LEF1, P = 4.24 × 10−10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10−9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10−8), 18q21.32 (PMAIP1, P = 2.51 × 10−8), 15q15.1 (BMF, P = 2.71 × 10−10) and 2p22.2 (QPCT, P = 1.68 × 10−8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10−18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10−8) and 5p15.33 (TERT, P = 1.92 × 10−7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism

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The major dietary sources of lutein in subjects with colon cancer and in control subjects were spinach, broccoli, lettuce, tomatoes, oranges and orange juice, carrots, celery, and greens. These data suggest that incorporating these foods into the diet may help reduce the risk of developing colon cancer.

Background: Reported revision rates for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) vary significantly. Several investigations examining revision rates for ESS have been limited by duration of follow-up, academic centers, or small surgeon cohorts. The objective of this study was to define the long-term revision rates for ESS and to determine those unique patient factors that increase the risk of revision ESS. Methods:The Utah Population Database was queried for Current Procedural Terminology codes for ESS from 1996 to 2016. Patient demographics and comorbid diagnoses were collected. Revision rates and risk factors for surgery were determined by Cox proportional hazard modeling. Results:A total of 29,934 patients were identified, with a mean length of follow-up of 9.7 years. The long-term revision rate was found to be 15.9%. The mean time between surgeries decreased with higher number of revision surgeries. The time between the first and second surgery was 4.39 years and the time between the fourth and fi h surgery decreased to 2.18 years. Female gender, older age at first surgery, nasal polyps, comorbid asthma, allergy, and a family history of CRS all increased the risk of requiring revision surgery (p < 0.001). Conclusion:The long-term revision rate for ESS exceeds 15% and the time between revision surgeries decreased with each additional surgery being performed. Unique patient factors increased the risk of requiring revision ESS. Understanding patients' risk for revision surgery may help physicians select and counsel patients with CRS undergoing ESS. C 2018 ARS-AAOA, LLC.

Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.